Pulmonary fibrosis is a devastating disease with mortality rates that exceed those of many malignancies. Models that fibrosis is largely driven by inflammation have not proven to translate into effective therapy with corticosteroids. Thus, new molecular insights into the mechanism of pulmonary fibrosis are needed. Wnt/(-catenin signaling is a major pathway required for cell differentiation decisions that maintain adult tissue homeostasis, and has recently been implicated in fibrosis. Since tissue fibrosis is thought to require both epithelial destruction and fibroblast activation, we hypothesize that Wnt/(-catenin signaling drives the fibrogenic phenotype by targeting proliferation, survival and differentiation in both lung epithelial cells and fibroblasts. In this proposal, we will establish a causal role for Wnt/(-catenin signaling in the bleomycin model for lung fibrosis, using mouse models that manifest attenuated (LRP5-/-) or enhanced (AXIN2-/-) (-catenin signaling (Aim 1). During the injury phase of the bleomycin model, we will determine whether activation of Wnt/(-catenin signaling is required for the survival of alveolar type 2 (AT2) epithelial cells and their ability to repair after lung injury (Aim 2). During the fibrogenic phase of the bleomycin model, we will determine whether the activation of Wnt/(-catenin signaling observed in fibroblasts promotes their proliferation and migratory activities. (Aim 3). We hypothesize that limited Wnt/(-catenin signaling activation promotes alveolar epithelial cell survival and differentiation, revealing an important protective role during the early stages of alveolar repair after injury. Sustained activation of Wnt/(-catenin signaling in fibroblasts, however, ultimately drives the fibrogenic phenotype by promoting their proliferation and migration. The findings of this proposal aim to demonstrate the first causal link between Wnt/(-catenin signaling and pulmonary fibrosis. By parsing the effects of Wnt/(-catenin signaling in both alveolar epithelial and fibroblast components, we will provide much needed insight into the instigating causes of fibrotic lung diseases. PUBLIC HEALTH RELEVANCE: Pulmonary fibrosis encompasses a broad class of diseases, which affect 5 million people world-wide and approximately two-hundred thousand people in the United States. From the onset of symptoms, the median survival time is only 28 months. There are currently no effective therapies for pulmonary fibrosis, and recent clinical trials have produced disappointing results. Thus, new insights into the mechanisms of pulmonary fibrosis are needed to generate novel therapeutic treatments.